Pharmacokinetics, pharmacodynamics, and prediction of developmental abnormalities

The purpose of this article is to review the application of pharmacokinetics and pharmacodynamics to risk assessment for developmental toxicants and to the development of predictive models of developmental toxicity. Physiologically based pharmacokinetic models require knowledge of the anatomic and physiological changes taking place during pregnancy and of how the potential developmental toxicant is distributed into differentiating and developing fetal tissues. Physiologically based pharmacokinetic models of varying levels of complexity have been proposed for rodent and human gestation. Models of pharmacodynamic behavior are less well developed, although structure-activity relationships have led to useful insights for certain specific classes of developmental toxicants. Development of biologically based dose-response models, which integrate pharmacokinetics and pharmacodynamics, is in its early phases. Although their development has proven to be complex, biologically based dose-response models have the potential to form the basis for a broader understanding of mechanisms of developmental toxicity and for broad predictive utility in developmental toxicity.